Edematous, Foreign Body Reaction, Osteolysis, Synovitis
Conditions
Keywords
total joint arthroplasty, synovitis, ALVAL (Aseptic Lymphocyte-Dominant Vasculitis-Associated Lesion), osteolysis, periprosthetic metallosis
Brief summary
This research study is being conducted to determine if taking oral (by mouth in pill form) Apatone®B (a combination of Vitamins C and K3) will reduce chronic joint discomfort and improve function of non-infected symptomatic postoperative total joint replacements.
Detailed description
To perform a prospective, randomized, double-blind clinical trial to determine if oral Apatone®B, an amalgam of vitamins C and K3, has a therapeutic efficacy beyond the conservative care customarily used to reduce inflammatory synovitis and to increase the functional capacity of proven non-infected symptomatic postoperative total joint replacements.
Interventions
DRUGPlacebo
Two capsules taken twice daily with meals
DRUGApatone®B
Two capsules taken twice daily with meals
Sponsors
Summa Health System
Crystal Clinic Orthopaedic Center LLC
IC-MedTech Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
* Postoperative Total joint replacement with osteoarthritis as the underlying pathology * Proven non-infected symptomatic Total Joint Arthroplasty (TJA) (joint implanted for \>12 months post-op) * Age (50 to 85 years of age); based on a 10% trim of the age distribution for Summa Health System TJAs (7/1/08-6/30/2009).
Exclusion criteria
* An infection of any kind (prior to, or during the study) * Rheumatoid arthritis as the underlying pathology * Cortisone injection received \<6 months prior to study enrollment * Insulin dependent diabetes * Diagnosed immunodeficiency * On dialysis or have poor kidney function * Anti-coagulant medication (e.g., Coumadin or \>100mg of Aspirin daily) * Anti-seizure medication (e.g., Dilantin) * Steroidal medication (e.g., Prednisone, Advair or Symbicort) * NSAIDS (e.g., Celebrex or Toradol); a 14-day washout period will be allowed * bisphosphonates (e.g., Fosamax, Actonel, Aredia, Didronel, Boniva or Reclast) * hormonal therapy (e.g., Estrogen, Progesterone or Testosterone) * Cancer (active or in remission) * Planned concurrent vitamins exceeding a standard daily multivitamin or exceeding the Recommended Daily Allowance (RDA) for individual vitamins if used alone; a 72 hour wash out period will be allowed * A glucose-6-phosphate dehydrogenase (G6PD) deficiency * Pregnant or lactating; females who are in their reproductive years must have a negative serum pregnancy * Lactose intolerant * Citric acid intolerant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Visual Analog Scale (VAS) | 13-weeks | Pain Visual Analog Scale (VAS) Scale range (0-100) A higher VAS score indicate worse knee pain |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Surrogate Endpoint Markers (SEBs) | 13 weeks | HSS = Hospital for Special Surgery Knee Score , KSS = Knee Society Knee Score. * Scale range HSS total: 100-90 Excellent; 80-89 Very Good; 70-79 Good; 60-69 Fair; below 60 Poor * Scale range HSS pain walking: No Pain 15; Mild Pain 10; Moderate Pain 5; Severe Pain 0 (\*\*this is an element of the HSS total) * Scale range KSS: 80-100 Excellent; 70-79 Good; 60-69 Fair; below 60 Poor |
| TGFBeta Levels | Baseline and 13 Weeks | The final synovial aspirates obtained from the symptomatic knee of each subject were analyzed using Quantikine and Pyrilinks-D enzyme-linked immunosorbent assay kits from R&D Systems (Minneapolis, MN) and Metra Biosystems (Mountain View, CA), respectively. Lower TGFBeta concentrations represent a better outcome. |
| Deoxypyridinoline Levels | Baseline and 13 Weeks | The final synovial aspirates obtained from the symptomatic knee of each subject were analyzed using Quantikine and Pyrlinks-D enzyme-linked immunosorbent assay kits from R&D Systems(minneapolis, MN) and Metra Biosystems (Mountain View, CA) respectively. Lower DPD concentrations represent a better outcome |
Countries
United States
Participant flow
Recruitment details
A total of 57 subjects were consented to participate.
Pre-assignment details
Following consenting, 6 subjects did not meet the study inclusion/exclusion criteria, thus never received the study drug. 1 - Abnormal Liver Panel: very low Hemoglobin/Hematocrit levels 1 - Glucose-6-phosphate dehydrogenase (G6PD) deficiency 3 - X-rays revealed loose or mal-positioned component(s) 1 - Prescribed steroids prior to study drug
Participants by arm
| Arm | Count |
|---|---|
| Oral Apatone®B An amalgam of Vitamins C & K3
Apatone®B: Two capsules taken twice daily with meals | 17 |
| Placebo Oral capsule of similar appearance and taste without Apatone®B
Placebo: Two capsules taken twice daily with meals | 21 |
| Total | 38 |
Baseline characteristics
| Characteristic | Placebo | Total | Oral Apatone®B |
|---|---|---|---|
| Age, Continuous | 65.4 years STANDARD_DEVIATION 9.6 | 63.9 years STANDARD_DEVIATION 9.7 | 62.1 years STANDARD_DEVIATION 9.5 |
| Height | 169.8 centimeters STANDARD_DEVIATION 8.6 | 170.6 centimeters STANDARD_DEVIATION 9.2 | 171.7 centimeters STANDARD_DEVIATION 9.9 |
| Initial Pain Visual Analog Scale (VAS) | 46.8 units on a scale STANDARD_DEVIATION 24.9 | 51.4 units on a scale STANDARD_DEVIATION 25.1 | 57 units on a scale STANDARD_DEVIATION 24.1 |
| Region of Enrollment United States | 21 Participants | 38 Participants | 17 Participants |
| Sex: Female, Male Female | 12 Participants | 21 Participants | 9 Participants |
| Sex: Female, Male Male | 9 Participants | 17 Participants | 8 Participants |
| Time elapsed since TKA | 4.0 years STANDARD_DEVIATION 3.3 | 3.3 years STANDARD_DEVIATION 2.9 | 2.5 years STANDARD_DEVIATION 1.9 |
| Weight | 100 kilograms STANDARD_DEVIATION 16.8 | 99 kilograms STANDARD_DEVIATION 18.5 | 96.7 kilograms STANDARD_DEVIATION 20.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 21 |
| other Total, other adverse events | 14 / 17 | 7 / 21 |
| serious Total, serious adverse events | 1 / 17 | 0 / 21 |
Outcome results
Primary
Pain Visual Analog Scale (VAS)
Pain Visual Analog Scale (VAS) Scale range (0-100) A higher VAS score indicate worse knee pain
Time frame: 13-weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Apatone®B | Pain Visual Analog Scale (VAS) | Baseline | 57 units on a scale | Standard Deviation 24.1 |
| Oral Apatone®B | Pain Visual Analog Scale (VAS) | 13 Weeks | 39.7 units on a scale | Standard Deviation 27.4 |
| Placebo | Pain Visual Analog Scale (VAS) | Baseline | 46.8 units on a scale | Standard Deviation 24.9 |
| Placebo | Pain Visual Analog Scale (VAS) | 13 Weeks | 39.1 units on a scale | Standard Deviation 29.1 |
Comparison: Change from baseline data.p-value: 0.0063paired t-test
Comparison: Changes from baseline datap-value: >0.05paired t-test
Secondary
Deoxypyridinoline Levels
The final synovial aspirates obtained from the symptomatic knee of each subject were analyzed using Quantikine and Pyrlinks-D enzyme-linked immunosorbent assay kits from R&D Systems(minneapolis, MN) and Metra Biosystems (Mountain View, CA) respectively. Lower DPD concentrations represent a better outcome
Time frame: Baseline and 13 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Apatone®B | Deoxypyridinoline Levels | Basline | 8.0 nmol/L | Standard Deviation 6 |
| Oral Apatone®B | Deoxypyridinoline Levels | 13 Weeks | 6.4 nmol/L | Standard Deviation 1.5 |
| Placebo | Deoxypyridinoline Levels | Basline | 5.9 nmol/L | Standard Deviation 1.3 |
| Placebo | Deoxypyridinoline Levels | 13 Weeks | 6.1 nmol/L | Standard Deviation 1.8 |
Comparison: Change from baseline datap-value: 0.01ANOVA
Comparison: Changes from baseline datap-value: >0.05paired t-test
Secondary
Surrogate Endpoint Markers (SEBs)
HSS = Hospital for Special Surgery Knee Score , KSS = Knee Society Knee Score. * Scale range HSS total: 100-90 Excellent; 80-89 Very Good; 70-79 Good; 60-69 Fair; below 60 Poor * Scale range HSS pain walking: No Pain 15; Mild Pain 10; Moderate Pain 5; Severe Pain 0 (\*\*this is an element of the HSS total) * Scale range KSS: 80-100 Excellent; 70-79 Good; 60-69 Fair; below 60 Poor
Time frame: 13 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Apatone®B | Surrogate Endpoint Markers (SEBs) | HSS Pain Walking- Baseline | 5.9 units on a scale | Standard Deviation 5.4 |
| Oral Apatone®B | Surrogate Endpoint Markers (SEBs) | HSS Pain Walking-13 Weeks | 9.1 units on a scale | Standard Deviation 6.2 |
| Oral Apatone®B | Surrogate Endpoint Markers (SEBs) | HSS Total-Baseline | 69.6 units on a scale | Standard Deviation 14.3 |
| Oral Apatone®B | Surrogate Endpoint Markers (SEBs) | HSS Total-13 Weeks | 76.6 units on a scale | Standard Deviation 16.7 |
| Oral Apatone®B | Surrogate Endpoint Markers (SEBs) | KSS Total Pain-Baseline | 56.2 units on a scale | Standard Deviation 19.4 |
| Oral Apatone®B | Surrogate Endpoint Markers (SEBs) | KSS Total Pain-13 Week | 65.3 units on a scale | Standard Deviation 20.1 |
| Placebo | Surrogate Endpoint Markers (SEBs) | KSS Total Pain-Baseline | 59.0 units on a scale | Standard Deviation 14 |
| Placebo | Surrogate Endpoint Markers (SEBs) | HSS Pain Walking- Baseline | 6.9 units on a scale | Standard Deviation 4.3 |
| Placebo | Surrogate Endpoint Markers (SEBs) | HSS Total-13 Weeks | 74.5 units on a scale | Standard Deviation 11.1 |
| Placebo | Surrogate Endpoint Markers (SEBs) | HSS Pain Walking-13 Weeks | 7.9 units on a scale | Standard Deviation 4.4 |
| Placebo | Surrogate Endpoint Markers (SEBs) | KSS Total Pain-13 Week | 63.0 units on a scale | Standard Deviation 18.4 |
| Placebo | Surrogate Endpoint Markers (SEBs) | HSS Total-Baseline | 71.9 units on a scale | Standard Deviation 11.6 |
Comparison: Change from baseline data (HSS pain walking)p-value: 0.0226paired
Comparison: Change from baseline data (HSS total score)p-value: 0.0375paired t-test
Comparison: Change from baseline data (KSS knee pain)p-value: 0.0391paired t-test
Comparison: Changes from baseline data (HSS pain walking)p-value: 0.2137paired t-test
Comparison: Change from baseline data (HSS total score)p-value: 0.1312paired t-test
Comparison: Change from baseline data (KSS knee pain)p-value: 0.1578paired t-test
Secondary
TGFBeta Levels
The final synovial aspirates obtained from the symptomatic knee of each subject were analyzed using Quantikine and Pyrilinks-D enzyme-linked immunosorbent assay kits from R&D Systems (Minneapolis, MN) and Metra Biosystems (Mountain View, CA), respectively. Lower TGFBeta concentrations represent a better outcome.
Time frame: Baseline and 13 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Apatone®B | TGFBeta Levels | Baseline | 3197.4 pg/mL | Standard Deviation 2793.5 |
| Oral Apatone®B | TGFBeta Levels | 13 Weeks | 2572.2 pg/mL | Standard Deviation 2879.7 |
| Placebo | TGFBeta Levels | Baseline | 2089.2 pg/mL | Standard Deviation 2879.7 |
| Placebo | TGFBeta Levels | 13 Weeks | 1572.2 pg/mL | Standard Deviation 1803.9 |
Comparison: Changes from baseline datap-value: 0.0083t-test
Comparison: Change from baseline datap-value: >0.05paired t-test